The goal of this program is to define molecular mechanisms which contribute to thrombus formation and dissolution. Information gained from these studies will be used to develop strategies for controlling thrombosis in vivo and designing tests for monitoring thrombotic events. Dr. David Loskutoff will study the structure, function and cellular biology of proteins that specifically bind to plasminogen activator inhibitor-1, and the importance of this process. The mechanisms by which theses proteins stabilize plasminogen activator-1 and the importance of this process in the regulation of fibrinolysis will be explored. Dr. Mark Ginsberg will define changes induced in the glycoprotein IIb/IIIa receptor of platelets following occupation by arg-gly-asp bearing ligands. This work will extend observations made with PMI-1, an antibody which recognizes a neo-antigenic site expressed on the occupied glycoprotein IIb/IIIa complex. Dr. Zaverio Ruggeri will define the structure and functional relationship of the von Willebrand Factor domains mediating binding of this molecule to collagen and heparin. Structural differences between von Willebrand Factor, fibrinogen and fibronectin which govern specificity of binding to adhesion receptors will be defined and development of peptides which block these interactions will be continued. Dr. Stephen Hanson will evaluate the effect of blocking ligand-platelet interactions on thrombosis in non-human primate models. Antibodies and peptides which selectively block different glycoprotein IIb/IIIa ligands as well as agents blocking von Willebrand Factor binding to glycoprotein Ib will be studied. Dr. John Griffin will study the two major plasma inhibitors of protein C, identify protein structural regions responsible for the interaction of activated protein C with these inhibitors, develop nw methods to characterize complexes of activated protein C with these inhibitors in blood and plasma, and will seek to identify variant protein C alleles. Dr. Laurence Harker will use activated protein C, synthetic inhibitors of thrombin, and hirudin to extend preliminary studies which indicate that thrombin is generally important in the formation of thrombus under either high or low shear flow conditions in vivo. Dr. Theodore Zimmerman will use antibodies with defined epitopes as probes of Factor VIII structure-function relationships. The results of antibody studies will be used in the design of mutant Factor VIII molecules to identify structures which mediate the different functions of Factor VIII.